Rethinking What It Means to Modify Parkinson's Disease: A New Definition for a New Era of Treatments

Table of Contents

• Key Points
• Background: Why This Matters
• Current Definitions of Disease Modification
• Challenges in Assessing Disease Modification
• The Role of Biomarkers and Staging
• New Therapies with Disease-Modifying Potential
• Targeting Causal Mechanisms and Immunomodulation
• Anti-Inflammatory Approaches
• Restorative and Regenerative Interventions
• The Need for a New Definition
• Three Examples of How a New Definition Changes Evaluation
• Clinical Implications for Patients
• Limitations and Open Questions
• Recommendations and Takeaways
• Frequently Asked Questions
• Source Information

Key Points

• A proposed broader definition: a disease-modifying therapy prevents, delays, halts, or reverses clinical progression that is meaningful to patients, physicians, and regulatory agencies.
• The aims of disease modification vary by stage: preventing first symptoms in prodromal disease, delaying progression in early motor disease, and preventing complications and decline later.
• Deep brain stimulation and dopamine infusions control symptoms but do not modify the disease, because core neuronal loss continues.
• A treatment cannot be judged disease-modifying by biomarkers alone, but validated biomarkers help separate symptomatic effects from disease-modifying ones.
• Longer observation periods may be needed to show benefit, especially in aggressive disease, where slowing may only appear after two or three years.

Background: Why This Matters

Parkinson's disease treatment today relies mainly on oral dopamine replacement therapy. This includes levodopa and other medications that work on dopamine pathways. Doctors also use non-dopaminergic oral medications, non-oral dopamine replacement, and surgical interventions to treat the typical motor and non-motor symptoms of the disease.

Levodopa and similar dopaminergic medications work well at first. They provide effective initial control of motor symptoms. However, their benefit significantly lessens over time. As Parkinson's disease progresses, patients frequently experience inadequate control of the cardinal motor features: tremor, rigidity, and bradykinesia (slowness of movement).

Patients also develop axial features. These include disturbances of speech, gait, and balance. Treatment-related motor complications commonly emerge as well. These include wearing-off phenomena with fluctuations in motor function and levodopa-induced dyskinesias (involuntary movements). These complications cause additional functional impairment and reduce quality of life.

At the same time, non-motor features become increasingly severe. These include fatigue, sleep disturbances, pain, neuropsychiatric symptoms, and cognitive deficits. These non-motor features are often refractory to current therapeutic interventions, meaning they do not respond well to available treatments.

These escalating challenges profoundly worsen quality of life. They increase caregiver burden. They also contribute significantly to the morbidity and mortality associated with advanced Parkinson's disease.

Given the inevitable progression of disease, the ability to modify the progression of Parkinson's disease remains a key unmet need. It is a priority for patients, clinicians, and scientists alike. Novel disease-modifying therapies may target the underlying pathology of Parkinson's disease. The aim is to address all clinically important disease manifestations. Alternatively, they may aim to preserve or restore specific functions, such as dopaminergic control of movement.

Interventions aimed at disease modification may therefore include approaches that directly address the core biological mechanisms of the disease. They may indirectly activate compensatory pathways. They may also restore lost cells, with varying impact on the underlying molecular basis of the disease.

To advance this field, it would be of great value to establish a holistic definition of disease modification. This definition would help meaningfully assess the potential of new disease-modifying therapies. This review explores existing definitions, assessment methods, and therapies in clinical development. It also considers patient and physician perspectives on what constitutes meaningful disease modification.

Current Definitions of Disease Modification

Recent expert opinions have considered a clinically applicable definition of disease-modifying therapy. This definition focuses on patients' own pathophysiological processes (the biological changes that cause disease), symptoms, and signs. It includes treatments that alter disease progression in several ways. They may address pathophysiological processes directly. They may improve compensatory responses. They may also reduce the severity or propagation of pathology in other ways.

Therefore, a treatment that delays, halts, reverses, or prevents progression of symptoms may be considered to have modified the disease. This applies if the effect can be reasonably ascribed to biological or structural changes in the brain. It applies regardless of whether the treatment has targeted the primary root causes of the disease.

The authors propose a reconsideration of interventions. This encompasses a return to a holistic and inclusive consideration of what is considered disease modification. This should include not only a rigorous research perspective. It should also include broader viewpoints from healthcare professionals and, importantly, people with lived experience of Parkinson's disease. The authors believe that a meaningful definition usable in clinical trials will advance progress. It will also support strategic pathways of engagement with regulatory agencies.

It is also important to incorporate into a new definition that the specific aims of disease modification in Parkinson's disease will vary with disease stages.

• In prodromal Parkinson's disease (the early phase before motor symptoms appear), preventing or delaying the first manifestation of motor and non-motor features should be considered disease modifying.
• Once motor symptoms manifest, a valuable aim may be reversing or delaying progression. The focus should be on increased functionality, preserved autonomy, and improved quality of life.
• In later stages, disease modification might be the prevention of motor complications of levodopa therapy. It might also be the prevention of further decline, including dementia, severe disability, and premature mortality.

The importance of constructing and operationalizing a definition of a treatment that is disease modifying versus symptomatic is complicated. This complexity arises from the knowledge that effective "symptomatic" approaches may achieve similar aims in at least some of these areas.

Therefore, when evaluating disease modification in clinical trials, perceived improvements may be caused by direct or indirect effects on underlying disease mechanisms and symptoms. For instance, deep brain stimulation and dopamine infusion therapies may provide control of dopamine-responsive features. However, they do not constitute direct disease modification, because the core neuronal loss continues.

Long-term observational studies suggest that deep brain stimulation delays the onset of late-stage disability milestones and improves quality of life. Even so, it does not modify the progressive pathobiology of Parkinson's disease.

Challenges in Assessing Disease Modification

Although the goal of preventing or curing Parkinson's disease may not be within immediate reach, varying degrees of disease modification may still be attainable. Consideration of how to measure disease modification based upon a newly evolving definition will therefore be critical. A lack of appropriate disease progression endpoints may have played a role in the negative results in previous clinical trials.

The need for a flexible approach is mandated due to the heterogeneity of Parkinson's disease. This heterogeneity applies both to clinical features and etiology (causes). Stratifying study participants by clinical phenotype, symptomatology, or staging by biological frameworks could benefit the ability of clinical trials to confirm or exclude the potential of new disease-modifying therapies. This means that clinical and biomarker measures may not be a "one size fits all" approach.

The first key challenge in trial design is to distinguish between symptomatic and disease-modifying effects of the investigational treatment. Several established trial designs aim to detect disease-modifying treatment effects. These include washout, delayed-start, randomized-withdrawal, and long-term parallel group designs. More recent adaptive approaches, such as multi-arm, multi-stage, and platform trials, may improve efficiency. They enable multiple candidate therapies or doses to be evaluated within a shared infrastructure.

However, in addition to trial design, defining and selecting the right endpoints may play an equally important role in a trial's ability to detect disease modification. Commonly reported clinical outcome measures used as primary endpoints have focused upon motor symptoms. These include the assessment of disease severity with the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) or one of its subscales. These measures can be influenced longitudinally by symptomatic treatment or disease modification.

A well-known example is the double-blind, delayed-start trial of high and low doses of rasagiline. This trial demonstrated that the low dose met primary efficacy endpoints for disease modification, whereas the high dose did not. Investigators speculated that the symptomatic benefit of the higher dose masked the disease modification signal. However, this was impossible to verify given the clinical trial data.

Demonstrating disease modification using slowly progressing changes in clinical outcomes, as assessed using the MDS-UPDRS, necessitates longer clinical observations than traditional trials testing symptomatic efficacy. This raises multiple challenges, including patient retention and accounting for inevitable concomitant medication changes.

Ideally, clinical observations will be supported using biomarker-based outcomes that will reliably reflect disease modification. The richest experience in incorporating biomarkers into clinical trials testing disease modification has been with neuroimaging. This includes nuclear medicine techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). These techniques offer minimally invasive evaluation of molecular targets, neurotransmitters, dopaminergic nerve loss, and network activity. They provide the promise to possibly support evaluation of potential disease-modifying therapies.

The Role of Biomarkers and Staging

Integrated patient staging systems have been proposed to incorporate validated biomarkers. These are not yet in use as primary endpoints in Parkinson's disease clinical trials evaluating disease-modifying therapies. Such systems include characterized α-synuclein seed amplification assays (tests that detect abnormal protein clumping) of defined sensitivity and specificity classifications. These assays help detect patients in the prodromal phase of the disease. Staging systems also incorporate imaging via a dopamine transporter scan.

However, significant shortcomings persist in applying staging systems based on α-synuclein aggregation. These include the need to meet or exceed current sensitivity and specificity standards. They must simultaneously consider the wide array of clinical presentations and the heterogeneity of Parkinson's disease progression. Testing requires either a cerebrospinal fluid sample or a skin biopsy. This testing is not yet validated as a suitable endpoint for clinical trials.

Furthermore, it may be premature for staging systems to solely emphasize α-synuclein aggregation. This is because it has been increasingly recognized that patients with Parkinson's disease exhibit multiple co-pathologies. These include amyloid-β, hyperphosphorylated tau, and transactive response DNA-binding protein 43. Rather, an adaptable and responsive framework is needed to harmonize future clinical and scientific efforts in Parkinson's disease.

Once validated, and this may be done in various stages and various cohorts, such classification and staging of patients may offer a biologic construct. This construct would serve as an operational system to treat patients who are more likely to benefit from specific treatments targeted to a defined biological process. It would allow treatment as early as possible and accelerate the development of disease-modifying therapies.

Another approach, such as quantified cell loss, may not be easily evaluated during life. It may not be easily correlated to symptom development in cohorts of those with Parkinson's disease. This could instead reinforce the need for research using medical imaging.

To ensure that biological shifts translate into tangible improvements for the individual, biomarkers must be calibrated against patient-reported outcomes and clinical scales. This calibration uses anchor-based methods. Under the proposed holistic definition, these biomarkers should be integrated with significant disease milestones. These milestones include the onset of falls, emergence of dementia, or admission to long-term care. They should also be integrated alongside objective digital health assessments.

By shifting the focus toward these high-impact events and real-world functional data, the evaluation of disease-modifying therapies can move beyond generic clinical scales. This allows for a more personalized assessment framework. This framework accounts for disease subtype, stage, and person-specific priorities. It ensures that "modification" is measured by its meaningful impact on a patient's life trajectory.

Finally, individuals with genetic forms of Parkinson's disease, or specific biomarker profiles denoting a particular dominant pathophysiology, may benefit from distinct disease modification assessments. Examples include clinical trials of leucine-rich repeat kinase 2 (LRRK2) inhibitors, β-glucocerebrosidase enhancers, or PINK1 or Parkin gene therapy. The biological mechanisms in these cases may be addressed directly using, for example, fluid-based biomarkers.

In addition, accumulating evidence suggests that in subsets of patients without known genetic risk variants, certain cellular phenotypes or biomarkers may indicate the involvement of these pathways in disease pathogenesis. This may help to stratify patients for pathway-specific treatments. For example, centrosomal cohesion deficit in blood cells of a subset of patients with Parkinson's disease supports the use of this biomarker. It could identify patients who may benefit from LRRK2-related therapeutics. Regardless of the original disease trigger, individually tailored treatment strategies can be developed to target specific and known aberrant pathways in genetically caused Parkinson's disease.

In summary, a treatment may not be considered disease-modifying based solely on biomarkers. However, the authors consider that appropriate biomarkers will add considerable value to developing disease-modifying therapies. These therapies will have a meaningful impact on patients. Their role will be key for distinguishing whether the impact of some therapies is symptomatic or disease-modifying.

New Therapies with Disease-Modifying Potential

The therapeutic pipeline for Parkinson's disease is currently undergoing a paradigm shift. It is moving away from late-stage symptom management toward early biological intervention targeting multiple points of the neurodegenerative cascade. An overview of key approaches is summarized below.

This section is intended as an illustrative, non-exhaustive overview of therapeutic classes that challenge traditional definitions of disease modification. The selected examples span biological pathway-targeting, immunomodulatory, restorative cell-based, and circuit/gene-delivery approaches. Each may require different evidence standards, biomarkers, and clinical endpoints to support a disease-modification claim.

Targeting Causal Mechanisms and Immunomodulation

Current trials, such as those for the monoclonal antibody prasinezumab, utilize immunotherapy to bind and clear toxic aggregates. Other "upstream" approaches include small molecules targeting the LRRK2 pathway (e.g., BIIB122). They also include antisense oligonucleotides (ASOs) designed to degrade LRRK2 messenger ribonucleic acid (mRNA). These therapies aim to stop the initial triggers of cell death before significant neuronal loss occurs.

Anti-Inflammatory Approaches

Neuroinflammation accelerates Parkinson's disease progression. Recognizing this, researchers are investigating GLP-1 receptor agonists (originally developed for diabetes) like lixisenatide and exenatide for their neuroprotective properties. Additionally, novel inhibitors of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome are being tested. These aim to reduce the chronic immune activation in the brain that contributes to ongoing neurotoxicity.

Restorative and Regenerative Interventions

For more advanced stages, the focus shifts to restoration. Cell therapies, such as bemdaneprocel (stem-cell-derived dopaminergic progenitors), aim to replace lost neurons in the putamen (a brain region involved in movement control).

Parallel to this, gene therapies use viral vectors called adeno-associated virus (AAV). These vectors either deliver growth factors like glial cell line-derived neurotrophic factor (GDNF) to support surviving neurons. Alternatively, they deliver enzymes such as glucosylceramidase to restore lysosomal function and attenuate α-synuclein aggregation.

The Need for a New Definition

Traditional clinical trials in Parkinson's disease have relied almost exclusively on motor scales, like the MDS-UPDRS, to determine success. However, this review highlights that these measures often fail to distinguish between a temporary "symptomatic boost" and a fundamental change in the disease course.

A new, holistic definition is helpful because it incorporates biological target engagement, sustained divergence of clinical paths, and patient-centered milestones.

Three Examples of How a New Definition Changes Evaluation

Below are three specific examples of how this redefined concept changes the way modern therapies are evaluated, in the authors' opinion.

1. Monoclonal antibody trials: Under traditional definitions, these trials have often been labeled as failures because they did not significantly lower motor scores within one year. However, a new definition focused on pathological slowing may be proposed. If an antibody successfully reduces the accumulation of toxic α-synuclein or slows the rate of dopamine transporter loss on imaging, it is "modifying the disease". This is true even if symptoms remain stable in some patients. Longer observation periods may also be needed to show benefit in more aggressive disease, in which slowing may only occur after the 2- or 3-year mark.
2. Cell therapies like bemdaneprocel: These pose a unique challenge because they add new dopamine-producing cells to the brain. This creates a symptomatic improvement that resembles that achieved by higher doses of levodopa. A traditional definition might fail to distinguish this from a drug effect. A new, holistic definition is helpful here because it shifts the focus to long-term integration and durability. Success is redefined as the survival of the graft (confirmed by F-DOPA positron emission tomography) and the postponement of late-stage milestones. These milestones include the onset of "OFF" periods or dyskinesia, which would typically emerge as the native disease progresses. As such, cell therapies may align primarily with the group of disease-modifying therapies.
3. Gene therapies: These approaches deliver therapeutic genes to specific brain regions. A new definition would evaluate whether the therapy changes the underlying disease trajectory, not just whether it improves symptoms temporarily.

Clinical Implications for Patients

This new definition of disease modification has several important implications for patients and their families.

• Broader recognition of benefit: Treatments that slow the disease without immediately improving symptoms may still be considered successful. This means patients may benefit from therapies even if they do not feel better right away.
• Focus on what matters most: The new definition prioritizes outcomes that patients actually care about. These include maintaining independence, avoiding falls, preventing dementia, and delaying the need for long-term care.
• Personalized assessment: The definition accounts for disease subtype, stage, and individual priorities. This means two patients with Parkinson's disease may have different treatment goals and different measures of success.
• Earlier intervention: The definition supports treating patients as early as possible, even in the prodromal phase before motor symptoms appear. This could potentially prevent or delay the onset of disabling symptoms.
• Recognition of genetic forms: Patients with genetic forms of Parkinson's disease may benefit from targeted therapies. These therapies address the specific biological mechanisms causing their disease.

Limitations and Open Questions

The authors acknowledge several limitations and open questions in this field.

• Biomarker validation: Current biomarkers, such as α-synuclein seed amplification assays, are not yet validated as suitable endpoints for clinical trials. They require either a cerebrospinal fluid sample or a skin biopsy, which may not be practical for all patients.
• Heterogeneity of disease: Parkinson's disease varies widely between patients in both clinical features and causes. A "one size fits all" approach to measuring disease modification is not appropriate.
• Co-pathologies: Many patients with Parkinson's disease have multiple types of brain pathology, including amyloid-β, tau, and TDP-43. Staging systems that focus only on α-synuclein may miss important aspects of the disease.
• Trial design challenges: Demonstrating disease modification requires longer observation periods than traditional trials. This raises challenges with patient retention and accounting for medication changes.
• Distinguishing symptomatic from disease-modifying effects: It remains difficult to determine whether a treatment's benefit comes from symptom relief or from actually changing the disease course.

Recommendations and Takeaways

Based on this review, the authors propose several key recommendations for the field.

1. Adopt a holistic definition: A disease-modifying therapy should be defined as a treatment with demonstrated ability to prevent, delay, halt, or potentially reverse clinical progression. This must be measured on outcomes that are meaningful and relevant to patients, physicians, and regulatory agencies.
2. Include patient-centered endpoints: Endpoints should include outcomes that can be appreciated in daily life and monitored by physicians during follow-up clinical visits. They should be supported by scientific rationale and biomarkers linked to pathological mechanisms and brain circuits.
3. Integrate biomarkers with clinical milestones: Biomarkers should be integrated with significant disease milestones. These include the onset of falls, emergence of dementia, or admission to long-term care. They should also be integrated with objective digital health assessments.
4. Account for disease stage: The specific aims of disease modification should vary with disease stage. In prodromal disease, prevention or delay of first symptoms is the goal. In early motor disease, reversing or delaying progression with focus on functionality is key. In later stages, preventing motor complications and further decline is paramount.
5. Develop personalized assessment frameworks: Assessment should account for disease subtype, stage, and person-specific priorities. This ensures that "modification" is measured by its meaningful impact on a patient's life trajectory.
6. Support longer observation periods: Longer observation periods may be needed to show benefit, especially in more aggressive disease. Slowing may only occur after the 2- or 3-year mark.
7. Engage patients and healthcare professionals: The definition should integrate the perspectives of patients, healthcare professionals, and researchers. This ensures that what matters most to patients is central to how treatments are evaluated.

In conclusion, the authors consider a disease-modifying therapy to be a treatment that has a demonstrated ability to either prevent, delay, halt, or potentially reverse clinical progression. This must be measured on measures that are meaningful and relevant to patients, physicians, and regulatory agencies. This would include endpoints that can be appreciated in daily life and monitored by physicians during follow-up clinical visits. These endpoints would also be supported by scientific rationale and biomarkers linked to pathological mechanisms and brain circuits.

Frequently Asked Questions

What counts as a disease-modifying treatment for Parkinson's disease?

A proposed broader definition says a disease-modifying therapy is any treatment that can prevent, delay, halt, or reverse clinical progression. That progression must be meaningful to patients, physicians, and regulatory agencies. This definition is wider than older ones, which focused mainly on whether a treatment targeted the underlying biological causes of the disease.

Why is the current definition of disease modification considered too narrow?

Older definitions focused on whether a treatment acted on the underlying disease processes. The authors argue this misses treatments that improve the body's compensatory responses or reduce how far pathology spreads. It also fails to capture what matters to patients, such as staying independent, avoiding falls, or delaying dementia, which a broader definition would include.

Does deep brain stimulation modify the disease?

No. Deep brain stimulation and dopamine infusion can control dopamine-responsive features, but they are not direct disease modification because the core neuronal loss continues. Long-term observational studies suggest deep brain stimulation delays late-stage disability milestones and improves quality of life, yet it does not modify the progressive pathobiology of Parkinson's disease.

Why have some Parkinson's treatment trials been called failures?

Trials have often relied on motor scales such as the MDS-UPDRS and were labelled failures when motor scores did not improve within about a year. Under a broader definition, a treatment that slows toxic protein accumulation or dopamine transporter loss on imaging could count as modifying the disease even if symptoms stay stable in some patients.

What is a biomarker and can it alone show a treatment works?

A biomarker is a measurable biological signal, such as an imaging scan or a protein test. A treatment cannot be considered disease-modifying based only on biomarkers. However, appropriate biomarkers add considerable value, especially for distinguishing whether a therapy's effect is symptomatic or truly disease-modifying, and they should be linked to outcomes patients feel.

Could treating Parkinson's earlier, before motor symptoms, help?

The proposed definition supports treating patients as early as possible, including the prodromal phase before motor symptoms appear. In that phase, preventing or delaying the first motor and non-motor features would count as disease modification. This could potentially prevent or delay the onset of disabling symptoms, though biomarkers for this stage are not yet validated as trial endpoints.

Will a disease-modifying treatment make me feel better right away?

Not necessarily. Under the broader definition, treatments that slow the disease without immediately improving symptoms may still be considered successful, so patients may benefit even if they do not feel better right away. Assessment would focus on outcomes patients care about, such as independence, falls, dementia, and delaying long-term care.

When should a patient with Parkinson's disease seek a second opinion about whether a treatment is truly disease-modifying?

A second opinion can help when it is unclear whether a therapy is changing the disease course or only easing symptoms. Levodopa and similar drugs control motor symptoms at first, but benefit lessens over time, and motor complications such as wearing-off and dyskinesias emerge. Treatments that slow progression without immediate symptom improvement may still be considered successful, and goals differ by stage, from delaying first symptoms to preventing falls, dementia, or long-term care. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Rethinking the concept of disease modification in an evolving Parkinson's disease treatment landscape.

Authors: Antonini A, Gross RE, De Leon M, Kwok K, Foltynie T, Höglinger G, Gasser T, Corvol JC, Pedrosa DJ, Volkmann J, Henchcliffe C.

Publication: Journal of Parkinson's Disease, 2026, pages 1–15

DOI: 10.1177/1877718X261481704

Article type: Review

Received: 1 December 2025; Accepted: 12 August 2026

Corresponding author: Claire Henchcliffe, University of California, Irvine, 200 S. Manchester Ave. Ste 206, Irvine, California USA. Email: chenchcl@hs.uci.edu

This patient-friendly article is based on peer-reviewed research. The original article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License, which permits non-commercial use, reproduction, and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page.